Circulating Galectin-3 Promotes Metastasis by Modifying MUC1 Localization on Cancer Cell Surface

Abstract

Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the ''protective shield'' of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (GalB1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis. [Cancer Res 2009;69(17):6799-806]

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…One of the Galectin-3 binding partners is oncofoetal Thomsen-Friedenreich antigen, which is on the transmembrane mucin protein MUC1 expressed by many metastatic cells (83). This interaction results in increased tumour cell homotypic aggregation to form microtumour emboli that prolong metastatic cell survival in the circulation by prevention of anoikis and enhanced heterotypic adhesion of the metastatic cells to the vascular endothelium (83)(84)(85).…”

Potential Tumor Biomarkers for Ovarian Cancer

“…Transmembrane mucins are positioned for mediation of communication between the extracellular milieu and the interior of cells. It has recently been proposed that the mucin covering of epithelia may be compromised when exposed to certain triggers, such as during processes involving elevated stress or remodeling (Kufe, 2009;Zhao et al, 2009), providing greater invasive potential. In this manner, a chronic inflammatory condition can theoretically turn the effects of transmembrane mucins against the cells they normally protect.…”

“…This loss of structural integrity of these towering glycoproteins leading to exposure of the protein core is likely a reason for compromised protection. Smaller hypoglycosylated variants appear to provide better access to epithelium for a number of diverse molecules that would otherwise be thwarted from engaging in cell surface interactions (Zhao et al, 2009). MUC1 additionally promotes EGFR activation by inhibiting its degradation (Pochampalli et al, 2007).…”

“…Sialylated TF is commonly found in hematopoietic and somatic cells, but the oligosaccharide is rarely observed in normal cells lacking sialyl groups (Schauer et al, 2011). In its desialylated form, this antigen is thought to be involved in triggering metastasis by stimulating interaction with galactoside-binding galectin-3 and exposing endothelial binding sites to cancer cells (Zhao et al, 2009). CA125) is another type of transmembrane mucin that mediates adhesive interactions in ovarian cancer.…”

Avaliação analítica de potenciais biomarcadores para câncer de bexiga em urina

“…2 Em pacientes com câncer com metástase, galectina-3 é ainda maior, sugerindo que pode estar relacionada com a metástase. 58,114 A proteína taxina-1 é codificada pelo gene TACC1 que encontra-se dentro de uma região cromossômica associada à tumorigênese. A maneira como essa proteína age na carcinogênese ainda não é conhecida, mas sua relação com diversos tipos de câncer é relatada em vários trabalhos.…”